Acoustic disruption of tumor endothelium and on-demand drug delivery for cancer chemotherapy

Abstract

Chemotherapy has been the most widely used treatment against cancer, however, is limited by its systemic toxicity as well as its resistance developed by tumors’ physical barriers. Herein, we propose a novel acoustically-mediated treatment regime to on-demand release therapeutics and disrupt tumor structures. By programming a high intensity focused ultrasound (HIFU) transducer, we can locally and digitally release gemcitabine (GEM) as well as open a local blood-tumor barrier or even tumor stroma to enhance intratumor drug delivery via acoustically-oscillating bubbles and liposomes. In our experiments, we modeled tumor endothelium by culturing a monolayer of murine endothelial cells (2H11) on transwell membrane. We locally disrupted the cultured endothelium to enhance drug penetration by using perfluorocarbon (PFC) liquid droplets as breaking probes and protoporphyrin IX (PPIX) hybridized liposomes as drug carriers. We also demonstrated an on-demand release of GEM by digitally triggering the break of drug carriers. Moreover, we validated the acoustic tumor endothelium disruption in vivo by monitoring penetration of dye (Evans blue) in solid tumors. Therefore, we present an acoustically-mediated delivery method that both releases drug on-demand locally and opens the blood-tumor barrier to enhance drug penetration. This sets the ground for further clinical cancer therapy to improve many systemic cancer treatments.